1. Field of the Invention
This invention relates generally to a novel method for enhancing penetration of physiologically active substances for cutaneous or transdermal delivery through epithelium which comprises the stratum corneum/epidermis and keratinizing mucous membranes. More specifically, it relates to a method and composition for disrupting the epithelial barrier function in a host which employs at least one agent selected from the group consisting of inhibitors of ceramide synthesis, an inhibitor of glucosylceramide synthesis, an inhibitor of acylceramide synthesis, an inhibitor of sphingomyelin synthesis, an inhibitor of fatty acid synthesis, an inhibitor of cholesterol synthesis, inhibitors of phospholipid, glycosphingolipid, including glucosylceramide, acylceramide and sphingomyelin degradation, a degradation enzyme of free fatty acid, ceramide, acylceramide, or glucosylceramides and sphingomyelin, and both inhibitors and stimulators of metabolic enzymes of free fatty acids, ceramide, and cholesterol.
2. Description of Related Art
The major function of the epithelium is that of a barrier to prevent the excessive loss of bodily fluids. If this barrier is disrupted or perturbed, it stimulates a variety of metabolic changes in the epithelium leading to repair of the barrier defect. While the barrier protects against external damage induced by such agents as ultraviolet radiation, desiccation, chemicals, and frictional or blunt trauma, it impedes the penetration of topically applied medicaments, nutrients, or other xenobiotics.
The epithelial barrier is a system of multilayered membrane lipid bilayers that exist throughout the intercellular spaces of the stratum corneum in epidermis and keratinizing mucous membranes. The bilayers in stratum corneum of epidermis consist of approximately equimolar ratios of three major lipid species: ceramides, free fatty acids, and cholesterol, as well as small, but critical, amounts of acylceramides. Keratinizing mucous membrane multilayered bilayers consist of approximately equimolar ratios of glucosylceramides, free fatty acids and cholesterol. These lipid species are synthesized in the subjacent nucleated cell layers of the epithelium. Following any type of barrier perturbation, an increase in lipid biosynthesis occurs, which leads to the recovery of barrier structure and function. The more extensive the perturbation of the barrier, the more active is the subsequent lipid biosynthetic response.
In addition to the long-standing approaches of hydration and occlusion, currently available percutaneous and transmucosal penetration enhancement technology relies on physical-chemical methods, such as solvents or detergents, and physical approaches, such as iontophoresis, electroporation, or sonophoresis. Typical solvents or detergents alter the physical properties of the multilayered lipid bilayers. Such agents include dimethylsulfoxide (DMSO), oleyl alcohol (OA), propylene glycol (PG), methyl pyrrolidone and AZONE(copyright) (dodecylazyl cycloheptan 2-one). For example, U.S. Pat. No. 4,177,267 discloses topical steroid compositions containing dimethylsulfoxide as an epithelial penetration enhancer. It is generally believed that many of these epithelial penetration enhancers fluidize the polar head group (e.g., DMSO) and/or nonpolar tail group (e.g., OA) domains within the multilayered lipid bilayers. Yet, some compounds with significant fluidizing effect have been shown to be incapable of substantially increasing epithelial permeability. While these methods enhance penetration of certain compounds by three- to five-fold, these methods are only relatively effective for smaller lipophilic and amphiphathic molecules. Hydrophilic compounds such as proteins or peptides do not penetrate in pharmaceutically useful quantities through the epithelia even when most of these permeation technologies are utilized.
Accordingly, there is a need for epithelial penetration enhancers capable of allowing and/or increasing the penetration of large and/or water-soluble molecules in therapeutically effective quantities. This invention addresses this need by providing methods and topical compositions for disrupting the epithelial barrier thereby facilitating the penetration of therapeutic known or potential molecules.
It has been discovered that a formulation comprising at least one agent selected from the group consisting of inhibitors of ceramide synthesis, inhibitors of glucosylceramide synthesis, inhibitors of acylceramide synthesis, inhibitors of fatty acid synthesis, inhibitors of cholesterol synthesis, and inhibitors of phospholipid, glycosphingolipid, acylceramide or sphingomyelin degradation, is very effective for disrupting epithelial barrier function in a host, and thereby enhancing penetration of a physiologically active substance administered topically.
In one aspect thereof, this invention provides a method for disrupting epithelial barrier function in a host in need of topical administration of a physiologically active substance which comprises applying to the skin of the host a barrier-disrupting amount of at least one agent selected from the group consisting of inhibitors of ceramide synthesis, inhibitors of acylceramide synthesis, inhibitors of glucosylceramide synthesis, inhibitors of free fatty acid synthesis, inhibitors of cholesterol synthesis, inhibitors of degradation of a phospholipid, glycosphingolipid, acylceramide or sphingomyelin, both inhibitors and a stimulators of steps of free fatty acid ceramide and cholesterol metabolism distal to these compounds, and degradation enzymes of free fatty acids, ceramides, acylceramides, or glucosylceramides and sphingomyelin, and both inhibitors and stimulators of metabolic enzymes of free fatty acids, ceramide, and cholesterol.
In another aspect, this invention provides a topical composition for disrupting epithelial barrier function in a host in need of topical administration of a physiologically active substance which comprises an epithelial barrier-disrupting amount of at least one agent selected from the group consisting of an inhibitor of ceramide synthesis, an inhibitor of acylceramide synthesis, an inhibitor of glucosylceramide synthesis, an inhibitor of sphingomyelin synthesis, an inhibitor of free fatty acid synthesis, and an inhibitor of cholesterol synthesis, inhibitors of phospholipid, glycosphingolipid, including glycosylceramide, acylceramide and sphingomyelin degradation, a degradation enzyme of free fatty acid, ceramide, acylceramide, sphingomyelin or glucosylceramides and both inhibitors and stimulators of metabolic enzymes of free fatty acids, ceramide, and cholesterol